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mandag den 11. februar 2013

TRPA1/TRPV4/PAR in inflammation/pain

Injury and inflammation trigger the activation of proteases from the circulation, immune cells and epithelial tissues that regulate cells by cleaving protease-activated receptors (PARs), members of a family of four G protein coupled receptors (GPCRs).

These G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain.

PAR2 is co-expressed with substance P and calcitonin gene-related peptide by a subpopulation of primary spinal afferent neurons that control neurogenic inflammation and pain transmission. Activation of PAR2 on sensory nerve endings evokes the local release of these neuropeptides, which stimulate extravasation of plasma proteins, infiltration of neutrophils and vasodilation (neurogenic inflammation). PAR2 activation also promotes the central release of neuropeptides that activate second order spinal neurons that transmit pain. These mechanisms contribute to painful inflammation of the intestine, pancreas and joints. Therefore, it is of considerable interest to understand the mechanisms by which PARs regulate the activity of nociceptive neurons.

Members of the TRP family, including TRPV1, TRPV4 and TRPA1 mediate neurogenic inflammation and pain, and are major down-stream targets of PAR2 . Activation of these non-selective cation channels stimulates the influx of extracellular Ca2+ ions and the release of neuropeptides in peripheral tissues and the spinal cord, which induces neurogenic inflammation and pain. During injury and inflammation, several factors are generated that can directly activate these channels. Elevated temperatures, protons and lipid mediators activate TRPV1, mechanical shear stress, osmotic stimuli and lipid mediators activate TRPV4, and products of reactive oxygen species and reactive prostaglandin metabolites activate TRPA1. However, indirect mechanisms, particularly those triggered by GPCRs, play a prominent role in TRP channel activation. Many GPCRs that induce neurogenic inflammation and pain indirectly regulate TRP channels, which mediate their pro-inflammatory and pronociceptive actions.

TRPV1 and TRPA1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons.

Peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously.

The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk.